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Biomedical subjects

O Simell

Publications and source records attributed to O Simell.

At least 163 records · Page 9Linked to original sources
PubMed1993

Skeletal manifestations of lysinuric protein intolerance. A follow-up study of 29 patients.

Lysinuric protein intolerance (LPI) is an autosomal recessive disease caused by defective transport of the cationic amino acids lysine, arginine, and ornithine at the cell membrane. About 80 patients with LPI have been described worldwide, almost half of them in Finland. The symptoms appear in early childhood as a failure to thrive, growth retardation, muscular hypotonia, and episodes of stupor after protein-rich meals. Twenty-nine Finnish patients (current median age 24.8 years, range 3.7-47.9 years) over a mean follow-up time of 18.1 years (range 1.2-27.2 years) had 57 fractures after minor trauma, mostly in childhood. Their 440 skeletal radiographs showed severe osteoporosis (13/29), controversially abnormal thickening of cortex of the metacarpals (7/29), or thin cortices of the long bones (5/29), endplate impression of vertebrae (8/29), rickets-like metaphyses (2/29), or early destruction of cartilage (3/29). Skeletal maturation was delayed by 1-5 years in 23 of 24 patients. There was no correlation between fracture incidence, radiological bone structure, and delayed skeletal maturation.

Adolescent↗
PubMed1993

Osteoporosis in lysinuric protein intolerance.

Lysinuric protein intolerance (LPI) is an autosomal recessive disease characterized by defective transport of cationic amino acids. Patients have an increased incidence of fractures and their skeletal radiographs show osteoporosis. The aim of the study was to characterize the osteopenia in LPI. Twenty-nine Finnish LPI patients (age range 3.7-44.4 years) were screened for parameters of bone metabolism. Morphometric analysis of bone was carried out in specimens of 9 patients. Collagen synthesis was studied with cultured skin fibroblasts (4 patients) and collagen fibril sizes (3 patients) were measured using electron microscopy. Most histological bone specimens (8/9) showed osteoporosis. Osteomalacia was excluded. Routine clinical laboratory tests were unrevealing. The concentrations of free hydroxyproline and type III procollagen N-propeptide in serum and the urinary excretion of hydroxyproline were increased in almost all patients during their growth and in about half of adult patients. Collagen synthesis in LPI fibroblast cultures was significantly decreased compared with that in age-matched controls at 5 (p < 0.01), 14 (p < 0.01) and still at 30 years (p < 0.01), whereas no difference was observed at the age of 44 years (p = N.S.). Osteoporosis in LPI might reflect defective matrix protein synthesis caused by protein deprivation and deficiency of cationic amino acids. Increased collagen turnover can also contribute to the osteoporosis.

Adolescent↗
PubMed1993

Glucose profiles in children two years after the onset of type 1 diabetes.

The relationship of 24-h glucose profiles to age, haemoglobin A1c (HbA1c), and C-peptide concentration was analysed in consecutive, unselected children who had developed Type 1 diabetes 2 years earlier. Seventy-seven children in four age groups (age 2-4 years, n = 9; 5-8 years, n = 14; 9-12 years, n = 26; and 13-17 years, n = 28) were studied. Each child was hospitalized for 2 days for the investigations. Mean blood glucose concentration was 9.7 +/- 4.1 (SD) mmol l-1 in children aged 2-4 years; 10.7 +/- 4.0 mmol l-1 in those aged 5-8 years; 11.3 +/- 3.4 mmol l-1 in those aged 9-12 years; and 9.8 +/- 3.3 mmol l-1 in those aged 13-17 years. Results were > 7.0 mmol l-1 in 69% (range 56-76%) and > 10 mmol l-1 in 49% (39-57%) of the measurements. Values decreased by 30% (21-43%) between 10 pm and 3 am. The nadir of the mean profiles of the groups was always at 3 am. Glucose concentration was mmol l-1 in 25% (14-50%), < 2.5 mmol l-1 in 9.6% (0-21%), and < 2.0 mmol l-1 in 2.7% (0-4.2%) of the children at 3 am; hypoglycaemia was most common in those aged 5-8 years. Of the four profile characteristics used, mean blood glucose predicted HbA1c (R2 = 24.7%, p < 0.00005, multiple linear regression analysis), and slightly more in combination with age (R2 = 32.0%, p < 0.00005).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

The first two years of type 1 diabetes in children: length of the initial hospital stay affects costs but not effectiveness of care.

The long-term costs of care and the effects of the length of the initial hospital stay on costs and effectiveness of the care of children with Type 1 diabetes are largely unexplored. A randomized prospective study was carried out wherein we shortened the length of the initial hospital stay from 23 +/- 4 days to 9 +/- 3 days in half of 61 consecutive children with newly diagnosed Type 1 diabetes. Metabolic control, psychosocial adjustment, and direct and indirect costs of care were compared during a 2-year follow-up. Having confirmed similar metabolic and psychosocial outcomes, we now report the costs of the two treatment modes. The costs of care of a child with Type 1 diabetes totalled 10,834 pounds and 6928 pounds in the long-term and short-term alternatives, respectively, during the 2-year follow-up (p < 0.001, one-way ANOVA). Direct costs accounted for 83% of the expenses in the long-term and 82% of the expenses in the short-term group; 73% and 56% of the direct and 78% and 72% of the indirect costs were incurred during the first month in the two groups, respectively. The first month's expenses were twice as high in the long-term than in the short-term group. Consumed hospital days and the parents' lost work time were the largest cost items in both groups. There were no significant differences in the cost items during the following 23 months. We conclude that the greater part of both the direct and the indirect expenditures were associated with the initial hospital stay.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Vascular addressins are induced on islet vessels during insulitis in nonobese diabetic mice and are involved in lymphoid cell binding to islet endothelium.

In the nonobese diabetic (NOD) mouse, lymphocytic and monocytic infiltration of the pancreatic islets leads to beta cell destruction. To investigate the mechanisms by which lymphocytes enter the NOD pancreas, pancreata were immunostained using monoclonal antibodies to a variety of adhesion molecules known to be involved in lymphocyte binding to vascular endothelium, an initial step in the migration of lymphocytes from blood into organized lymphoid and inflamed tissues. These adhesion molecules include: lymphocyte homing receptors involved in tissue-selective binding of lymphocytes to peripheral lymph node (L-selectin) or mucosal lymphoid tissue (LPAM-1, alpha 4 beta 7-integrin) high-endothelial venules (HEV); and HEV ligands peripheral vascular addressin (PNAd) and mucosal vascular addressin (MAdCAM-1). In NOD pancreata, alpha 4 beta 7 is expressed on most infiltrating cells at all stages of insulitis, whereas L-selectin expression is more pronounced on cells in the islets at later stages. During the development of insulitis, MAdCAM-1 and to a lesser extent PNAd became detectable on vascular endothelium adjacent to and within the inflamed islets. The Stamper-Woodruff in vitro assay was used to examine lymphoid cell binding to such vessels. These functional assays show that both the mucosal (MAdCAM-1/alpha 4 beta 7) and the peripheral (PNAd/L-selectin) recognition systems are involved in this binding. Our findings demonstrate that expression of peripheral and mucosal vascular addressins is induced on endothelium in inflamed islets in NOD pancreas, and that these addressins participate in binding lymphoid cells via their homing receptors. This suggests that these adhesion molecules play a role in the pathogenesis of diabetes in these mice by being involved in the migration of lymphocytes from blood into the inflamed pancreas.

Animals↗
PubMed1993

Somatostatin regulation of beta-cell function in the normal human fetuses and in neonates with persistent hyperinsulinemic hypoglycemia.

To investigate the insulin-inhibitory effects of somatostatin during fetal development, and the defective regulation of insulin release in persistent hyperinsulinemic hypoglycemia of infancy (PHHI), we made perifusion experiments with islet-like cell clusters obtained from 14 human fetal pancreases (HFP) before 20 weeks of gestation and 6 neonates pancreatectomized because of PHHI (5 cases of diffuse and 1 adenomatous islet cell hyperplasia). Somatostatin-14 (600 nmol/L) suppressed insulin release only marginally (20% and 25% suppression in 2 and 20 mmol/L glucose, respectively) in HFP, whereas supplementation of the perifusate with 14 nmol/L glucagon potentiated the suppression to 57%. Somatostatin-28 (600 nmol/L) caused a 35% inhibition in insulin release from the HFP. In static incubation of HFP, somatostatin-14 caused a weak dose-dependent inhibition of insulin release, but had no effect on (pro)insulin biosynthesis. In the PHHI infants, somatostatin infusion suppressed hyperinsulinemia effectively before pancreatectomy. In vitro, 600 nmol/L somatostatin-14 suppressed insulin release clearly better than in the HFP experiments (35-61% inhibition). Glucose (20 mmol/L) induced a 2- to 3-fold increase in insulin release in two clinically mild cases of PHHI, but no response at all in the four others. We conclude that human fetal beta-cells are relatively insensitive to somatostatin, possibly because of low cellular cAMP levels. Furthermore, insulin release from PHHI cells is poorly stimulated by glucose but effectively blocked by somatostatin, supporting the concept of somatostatin deficiency in PHHI.

Abortion, Induced↗
PubMed1993

Pulmonary manifestations in lysinuric protein intolerance.

STUDY OBJECTIVES: To evaluate the pulmonary manifestations and the course of acute respiratory insufficiency associated with lysinuric protein intolerance (LPI). DESIGN: Retrospective review of clinical data and chest radiographs (total 225) obtained during the lifetime follow-up of 31 LPI patients. About half of the 25 patients without respiratory symptoms underwent high-resolution computed tomography (HRCT) of the lungs, radionuclide perfusion imaging, whole body plethysmography, and diffusing capacity measurements. PATIENTS: Thirty-one Finnish patients with LPI. RESULTS: During the follow-up period, four children with LPI died in respiratory insufficiency, 1 adult had an episode of respiratory insufficiency, and another had chronic symptoms, whereas 25 patients remained symptom-free. The radiologic findings in acute progressive respiratory insufficiency were uniform: at first, reticulonodular interstitial densities and, later on, progressive airspace disease. At autopsy, three patients showed pulmonary alveolar proteinosis and one had pulmonary hemorrhage and cholesterol granulomas. One adult had reversible respiratory insufficiency with signs of bronchiolitis obliterans, another adult had recurrent episodes of chest pain, dyspnea, and hypoxia. Of the symptom-free patients, one third (8 of 25) had signs suggestive of pulmonary fibrosis evidenced on chest radiographs and two thirds (8 of 14) had signs evidenced by HRCT films. Most symptom-free patients showed mild abnormalities either in perfusion imaging (9 of 12) or in function tests (8 of 12). CONCLUSION: In childhood, patients with LPI are highly predisposed to develop pulmonary hemorrhages and alveolar proteinosis. Interstitial lung densities may precede the acute phase. Most adult LPI patients show radiologic signs of interstitial lung disease but only a few show clinical impairment.

Adult↗
PubMed1993

Endothelial cell-binding properties of lymphocytes infiltrated into human diabetic pancreas. Implications for pathogenesis of IDDM.

In IDDM, mononuclear cells accumulate in the islets of Langerhans and destroy insulin-producing beta-cells. To study the mechanisms that control extravasation of circulating mononuclear cells into the pancreas, we examined the phenotype of vascular endothelium of the pancreas, propagated a T-cell line from pancreatic islets at the onset of the disease and compared endothelial binding of this cell line in vitro to vascular endothelium in different body regions. The adhesion molecules expressed on the resulting T-cell line and the functional binding capacity of these cells to the endothelium of the normal and diabetic pancreas, mucosa-associated lymphatic tissues, and regional and peripheral lymph nodes were studied. We present evidence of pancreatic endothelial activation in diabetes, leading to endothelial morphology typical for HEVs and accompanying local increase in extravasation of mononuclear cells into the pancreas. Endothelial-cell binding experiments with the T-cell line showed strong adherence of the cells to the endothelium of diabetic pancreas and mucosal lymphoid tissue. The cell line was uniformly CD4-positive, TCR V beta 5.1-positive, LFA-1-positive (CD 11a/CD18), VLA-4 alpha-positive (CD 49d), and CD 44-positive but negative for L-selectin (peripheral lymph node homing receptor). The pancreatic or control cell lines showed no binding to vessels of normal pancreas, and the binding of the pancreatic cell line to the endothelium of peripheral lymph node was weak. Our results suggest that lymphocyte-endothelial cell interactions are important for the accumulation of inflammatory mononuclear cells into the pancreas and imply that lymphocytes derived from the mucosal lymphoid tissue may be involved in the pathogenesis of IDDM.

Cell Adhesion↗
PubMed1992

Mumps and Coxsackie B3 virus infection of human fetal pancreatic islet-like cell clusters.

Islet-like cell clusters (ICCs) prepared from human fetal pancreases were infected with mumps or coxsackie B3 virus. Double-labeled antibody technique showed that the viruses infected both insulin-secreting and other pancreatic cells and that secretion of immunoreactive insulin into the culture medium of the mumps virus-infected cells had already ceased on day 7. The mumps virus-infected ICC clusters produced virus for 14 days, and the mumps virus antigen was detected in the ICCs through the whole 22-day observation period. The coxsackie B3 virus-infected ICCs contained cells highly positive for viral antigen during the first 2 days after infection, and the infectious virus was detected in the culture medium for 22 days. This in vitro model indicates that mumps and coxsackie B3 viruses infect human fetal pancreatic endocrine cells and are able to alter beta-cell function. Coxsackie B3 virus infection in ICCs is lytical and seems to lead to rapid cell destruction, but long-lasting, restricted mumps virus infection in human fetal pancreatic ICCs offers an interesting model to study the effects of viral infection in the endocrine pancreas and beta cell.

Cells, Cultured↗
PubMed1992

Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus.

Current knowledge of the phenotype of mononuclear cells accumulating in pancreatic islets in insulin-dependent diabetes (IDDM) and factors determining their homing into the pancreas is limited. Therefore, a pancreas obtained at the onset of IDDM was studied in detail. Cryostat sections were stained for mononuclear cell types, T cell receptor subtypes, and adhesion molecules of vascular endothelium and studied by immunofluorescence microscopy, and peripheral blood mononuclear cells were phenotyped using flow cytometry. Monocytes/macrophages (lysozyme- or CD 14-reactive cells) were identified among other mononuclear cell types in islet infiltrates. V beta 8-positive T cells were overrepresented, but T cells with other V beta s studied (V beta 5, V beta 5.1, V beta 6, V beta 12) were also found. The vascular endothelium of the islets and many small vessels nearby islets strongly expressed intercellular adhesion molecule-1, whereas vascular cell adhesion molecule-1 and E-selectin were totally absent. We conclude: (a) that increased expression of intercellular adhesion molecule-1 on vascular endothelium may increase endothelial adhesion of mononuclear cells and enhance their accumulation in the pancreas during diabetic insulitis; (b) that T cells with certain T cell receptors can be enriched in infiltrated pancreatic islets; and (c) that macrophages and antigen-specific CD 8-positive T cells are involved in pancreatic beta cell destruction at the onset of IDDM.

Antigens, CD↗
PubMed1991

Randomised prospective study of short-term and long-term initial stay in hospital by children with diabetes mellitus.

To assess how an isolated change in the pattern of care influences outcome of care and hospital use, a randomised prospective 2-year study was done in which 31 of 61 consecutive children with newly diagnosed insulin-dependent diabetes mellitus (IDDM) were admitted to hospital at disease onset for about a week and compared with the other 30 children who were admitted for about 4 weeks. Insulin treatment and education about diabetes were similar in the two groups. Duration of initial stay in hospital had no effect on metabolic control during the 2 years but time since diagnosis was significant with respect to effect on haemoglobin A1 (p = 0.001), haemoglobin A1c (p = 0.004), and insulin dose (p less than 0.001). At 2 years, 45% of the children in the short-term group and 29% in the long-term group were C-peptide positive (p = NS); C-peptide positivity correlated with age. A change in the pattern of care of children with IDDM, led to a pronounced decrease in hospital use by this patient group. Irrespective of the length of initial stay in hospital, equally good metabolic control was obtained in both groups for 2 years.

Adolescent↗
PubMed1991

Lack of glucose-induced functional maturation during long-term culture of human fetal islet cells.

To investigate the long-term effects of glucose on the function of human fetal islets we cultured islet-like cell clusters (ICC) obtained from 12 human fetuses with a mean age of 16.1 weeks in media containing 2.8, 11.1 or 16.7 mM glucose. On the 8th day of culture, the ICC that had been maintained in 16.7 mM glucose contained 60% less insulin than the ICC cultured in 2.8 mM glucose. However, insulin release was similar in both groups, and was not affected by a 24-h incubation in high vs. low glucose. Also (pro) insulin biosynthesis was not significantly affected. During a 24-day culture period, the total release of insulin and glucagon was similar in all glucose concentrations. The ICC released about 75% of their insulin content but only 15% of their glucagon content during the last 48 h of the 24-day culture period, again regardless of glucose concentration in media. Insulin release was insensitive to acute glucose and leucine challenges in perifusion experiments after culture for 1, 5, 8 or 16 days in 11.1 mM glucose, whereas glucagon was always a potent stimulus. In conclusion, the function of cultured young human fetal islet cells is remarkably independent of glucose, even during prolonged exposure. Moreover, the primary role of glucagon in fetal life may be that of a paracrine stimulator of beta-cell function.

Arginine↗
PubMed1991

Children in sauna: hormonal adjustments to intensive short thermal stress.

Hormonal response to Finnish sauna bath was investigated in 20 prepubertal children (age 5-10 years). Blood leukocyte count, plasma potassium, serum aldosterone, growth hormone and prolactin concentrations increased; plasma volume, plasma sodium, catecholamines, serum antidiuretic hormone, atrial natriuretic peptide (ANP), cortisol, and thyrotropin concentrations remained unchanged during sauna bath. One hour after sauna, serum thyrotropin, atrial natriuretic peptide and blood glucose concentrations decreased, whereas the rest of the hormones remained unchanged. Our results implicate that maintenance of homeothermia resulted in moderate hormonal changes in children during Finnish sauna bath which indicate similar adequate hormonal thermoregulatory adjustment as previously documented in adults.

Catecholamines↗
PubMed1990

Tuberous sclerosis and infantile spasms.

The short- and long-term outcome and special problems of 24 children with infantile spasms and tuberous sclerosis (TS) was studied. The diagnosis of TS is frequently missed: white spots on the skin have to be carefully looked for. In the present study, these spots were always found, and calcifications or hypodense areas of the brain were revealed by CT scans before one year of age. In addition to epilepsy, manifestations of TS included: giant cell astrocytoma, iridic heterotopia, cardiac rhabdomyoma, brain cysts, polycystic kidneys with severe arterial hypertension, retinal phakomas, angiofibroma and white spots on the skin. Long-term outcome was poor. None of the children had normal intelligence and all but one had epilepsy, which was often intractable. Behavioural problems were common. The prognosis, in terms of later intelligence, epilepsy and behavioural problems, was worse than in those with 'idiopathic' infantile spasms or in those with simultaneous neurological disorders. An early diagnosis of TS in patients with infantile spasms clarifies the prognosis and avoids some of the hazards of ACTH therapy. TS children have a high relapse rate after ACTH therapy, so prolonged courses may be indicated.

Adolescent↗
PubMed1989

Hormonal background of the hypertension and fluid derangements associated with adrenocorticotrophic hormone treatment of infants.

We studied the hormonal background of the fluid derangements and arterial hypertension associated with adrenocorticotrophic hormone (ACTH) treatment for infantile spasms in ten infants aged 5-22 months. They received a 6 week course of (carboxymethyl-cellulose-)ACTH: 80 IU at 0800 hours daily in weeks 1-3, then tapering, and termination at the end of week 6. The infants showed large, variable increases in 24 h urine cortisol during treatment. The mean plasma cortisol concentration (24 h after ACTH injection) was not significantly increased, but was correlated with the relative dose of ACTH. The mean plasma aldosterone concentration decreased. No significant change occurred in plasma renin activity (PRA), or in the concentrations of renin substrate (RS) or arginine vasopressin (AVP). Seven infants developed arterial hypertension, which was severe in three. This severe hypertension was associated with the highest relative ACTH doses and the highest plasma RS and cortisol concentrations. In the group as a whole, systolic blood pressure correlated with plasma RS and cortisol concentrations, but not with the other parameters. At the end of treatment urine and plasma cortisol dropped below the pretreatment levels and stayed low for greater than 2 weeks. There was a sharp peak in PRA and plasma aldosterone concentration, and a decrease in plasma RS. Plasma AVP levels dropped markedly. The mean body weight increased sharply and urine flow decreased. Mean plasma electrolyte levels remained unaltered. The danger at termination of ACTH treatment appears to be associated with a sudden transition from hypercortisolism to hypocortisolism, activation of the renin-angiotensin-aldosterone axis, and suppression of AVP secretion.

Adrenocorticotropic Hormone↗
PubMed1989

Comparison of ornithine metabolism in hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome, lysinuric protein intolerance and gyrate atrophy fibroblasts.

We measured L-ornithine oxidation in cultured skin fibroblasts from seven patients with hyperornithinaemia-hyperammonaemia-homocitrullinuria (HHH) syndrome (McKusick 23897), and compared it with oxidation by ornithine aminotransferase deficient gyrate atrophy (McKusick 25887) cells and lysinuric protein intolerance (McKusick 22270) cells in which there is an ornithine transport abnormality at the plasma membrane. Net uptake of ornithine is not abnormal in intact HHH cells. Ornithine oxidation was depressed in HHH and gyrate atrophy cells but not in lysinuric protein intolerance cells; the latter finding suggests there is no significant mitochondrial defect in lysinuric protein intolerance cells. Since HHH cells have intact ornithine aminotransferase, impaired oxidation is compatible with deficient penetration of ornithine into mitochondria in this disease. We could not demonstrate a gene dosage effect in oxidation values.

Amino Acid Metabolism, Inborn Errors↗